Control of epithelial immune-response genes and implications for airway immunity and inflammation.
A major goal of our research is to understand how immune cells (especially T cells) infiltrate the pulmonary airway during host defense and inflammatory disease (especially asthma). In that context, we have proposed that epithelial cells lining the airway provide critical biochemical signals for immune-cell influx and activation and that this epithelial-immune cell interaction is a critical feature of airway inflammation and hyperreactivity. In this brief report, we describe our progress in defining a subset of epithelial immune-response genes the expression of which is coordinated for viral defense both directly in response to replicating virus and indirectly under the control of a specific interferon-gamma signal transduction pathway featuring the Stat1 transcription factor as a critical relay signal between cytoplasm and nucleus. Unexpectedly, the same pathway is also activated during asthmatic airway inflammation in a setting where there is no apparent infection and no increase in interferon-gamma levels. The findings provide the first evidence of an overactive Stat1-dependent gene network in asthmatic airways and a novel molecular link between mucosal immunity and inflammation. The findings also offer the possibility that overactivity of Stat1-dependent genes might augment a subsequent T helper cell (Th1)-type response to virus or might combine with a heightened Th2-type response to allergen to account for more severe exacerbations of asthma.
Holtzman
M J
MJ
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Look
D C
DC
Sampath
D
D
Castro
M
M
Koga
T
T
Walter
M J
MJ
D000818:Animals; D001249:Asthma / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics / Q000276:immunology; D007249:Inflammation; D009297:Nasal Mucosa / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology